A characteristic pathology of Alzheimer's Disease is the build up of insoluble amyloid plaques in the brain. These proteinaceous plaques are composed of a 4 KDa, 42 amino acid fragment of β-Amyloid Precursor Protein (APP) and is termed Amyloid β-peptide (Aβ). The mechanism of Aβ production is hence of critical importance in understanding the onset and progress of Alzheimer's Disease. It has been shown that Aβ is derived from the proteolytic cleavage of a larger protein, β-amyloid precursor protein (APP). Two enzymes are responsible for this cleavage; first, the enzyme β-secretase cleaves APP at residue 671 (770aa isoform of APP numbering) and then γ-secretase cleaves at residue 716. More recently, the novel transmembrane aspartic protease BACE has been identified as being β-secretase. This protein is now a significant target in a therapeutic approach to Alzheimer's Disease. In rare cases of Alzheimer's Disease that are hereditary (Familial Alzheimer's Disease (FAD)) the disease phenotype has been isolated to mutations in the β-Amyloid Precursor Protein. One particular cohort, the ‘Swedish mutation’, exhibits a double mutation at the β-secretase cleavage site.
Based upon the role of BACE in Alzheimer's Disease, the elucidation of the three-dimensional structure of BACE, as well as its site of binding with APP, would have important implications in the treatment and/or prevention of Alzheimer's Disease and similar diseases associated with the presence of insoluble amyloid plaques composed the 42 amino acid fragment of APP in the brain.